Premature rupture of membranes (PROM) during the second and early third trimester of human pregnancy is often caused by rhexis or rupture of the amnion, especially in the area in contact with the uterine cervix. Rhexus of the amnion may be caused by physical weakening of the amnion, elevation of intrauterine pressure, and dilation of the cervix. Infection may accompany each of these conditions, all of which interact with each other.
Although the fetal membrane is normally very strong, it is possible for it to become mechanically fragile due to exposure to bacteria or infection. Resistance to infection depends on natural physiologic and mechanical barriers such as the endocervical mucus plug, intact fetal membranes and antimicrobial properties of amniotic fluid. PROM destroys those barriers. If PROM is left untreated, labor ensues, and the fetus is delivered with premature function of various organs. Therefore, it is desirable to prolong the gestation of the fetus.
Typically, a patient who has suffered premature membrane rupture is immobilized in bed and sometimes given a tocolytic agent and an antibiotic. This treatment has often not proved sufficient to prevent maternal and fetal infections or labor, thus still often resulting in premature birth. Thus, while the infusion of antibiotics and other agents may be helpful, it would be more effective to provide some sort of physical plug or barrier to ascending infection. Such a barrier would also prevent the leakage of amniotic fluid out of the amniotic sac and aid in prolonging the gestation.
The need for such a barrier or sealant for fetal membranes is especially important for iatrogenic preterm premature rupture of the fetal membranes (iPPROM). iPPROM often results as an adverse complication from fetal diagnostic or therapeutic interventions which may occur during the second and third trimesters of human pregnancy. These diagnostic and therapeutic interventions can be invasive, and can require surgery or other procedures with large diameter fetoscopes (an instrument inserted into the uterus for such things as visualizing the fetus, taking tissue samples, or performing fetal surgery). Such invasive techniques are frequently complicated by amniotic fluid leakage, separation of amnion and chorion, or even frank iatrogenic preterm premature rupture of the fetal membranes (iPPROM).
Fetoscopic procedures often have rates of iPPROM ranging between 6 to 45%,1 although the iPPROM rates can me much higher. For instance, in a trial of fetal endoscopic tracheal occlusion for severe congenital diaphragmatic hernia, a 100% iPPROM rate was reported.2 Since these procedures are usually performed in the second trimester of pregnancy, iPPROM usually occurs at an early gestational age, and can lead to premature birth of the baby or other serious complications to the mother and baby. Hence, the associated morbidity and mortality may compromise the expected benefits of the intervention. iPPROM is therefore a very serious complication for prenatal fetal surgery.
Clinically, measures of plugging membranes after established rupture as well as of preventive plugging of fetoscopic access sites have been undertaken, as reviewed previously.3,4 Recent literature argues the risks and benefits of tocolytic agents, antibiotics, and corticosteroid injections primarily for delaying delivery, preventing intraamniotic infection, and enhancing fetal maturity, respectively, in the event of almost certain preterm delivery. However, to date, no true accepted treatment for iPPROM or PROM exists.
For closure after obvious iatrogenic rupture, intra-amniotic injection at the puncture site of maternal platelets mixed with fibrin cryoprecipitate (‘amniopatch’) has evolved as promising route to seal.5,6 However, the sudden activation of a large number of platelets in the amniopatch was accounted for otherwise unexplained fetal demise in some cases.5 But increasing efforts have been concentrated on taking prophylactic measures prior to rupture rather than therapy after established or symptomatic rupture of the membranes.
Several preventive plugging methods using dry collagen and gelatin plugs or liquid blood-derived sealants have already been clinically investigated.7,8 Preliminary experience supports this prophylactic intervention for prevention of iPPROM. A 2006 report on a 27 patient cohort found a 4.2% rate of postoperative PPROM upon gelatin plug (Gelfoam) insertion upon port retrieval in endoscopic fetal surgery.7 
In another small clinical study, sequential injection of platelets, fibrin glue and powdered collagen slurry directly to the puncture site successfully prevented amniotic fluid loss after endoscopic procedure.8 Still, the positive outcome with these methods await to be reproduced in other centers. Of note, collagen fleece plugs (Lyostypt™) are now routinely used for prophylactic plugging of iatrogenic membrane defects following fetoscopic endoluminal tracheal occlusion for in utero therapy of congenital diaphragmatic hernia.
Other prophylactic plugging techniques such as scaffold-type plugs manufactured directly from decellularized amnion tissue have been so far only evaluated in animal models.9,10 Further, laser welding, pre-emptive placement of synthetic surgical sealants before fetoscopic access, direct injection into amniotic fluid of fibrinogen/thrombin-based tissue sealant, and sealing with platelet-rich plasma were also evaluated in laboratory settings.11,12,13,14 
Accordingly, there is a long-felt, unmet need for biocompatible, non-toxic and durable sealants for membrane repair that provide a physical barrier to amniotic fluid.